Nuclear factor .kappa.B (NF-.kappa.B) is a eukaryotic transcription factor that exerts pleiotropic effects on diverse cellular genes involved in the immediate early steps of immune activation and inflammation. Additionally, NF-.kappa.B has been implicated in the transcriptional activation of several viruses, including HIV-1 (for a review, see Siebenlist et al. Annu. Rev. Cell. Biol. 10:405-455 (1994)).
Nuclear expression and consequent biological action of the eukaryotic NF-.kappa.B transcription factor complex is tightly regulated through its cytoplasmic retention by an ankyrin-rich inhibitory protein termed I.kappa.B.alpha.. I.kappa.B.alpha. specifically binds to and masks the nuclear localization signal of the Rel A subunit of NF-.kappa.B, thereby effectively sequestering this transcription factor complex in the cytoplasm. Specific cellular activation signals lead to the rapid proteolytic degradation of I.kappa.B.alpha. and the concomitant nuclear translocation of NF-.kappa.B. Such signals include, for example, mitogens such as phorbol esters, cytokines such as tumor necrosis factor alpha (TNF-.alpha.) and interleukin-1 (IL-1), and the Tax protein from the type I human T cell leukemia virus (HTLV-1). Activation of NF-.kappa.B by these and other inducers appears to involve the transient phosphorylation and subsequent proteolytic degradation of I.kappa.B.alpha. which permits nuclear translocation of the liberated NF-.kappa.B complex. Nuclear expression of the NF-.kappa.B complex leads to transcriptional activation of a broad array of cellular genes involved in immune stimulation, inflammation, and cell growth.
Mutant I.kappa.B.alpha. molecules have been constructed to investigate the regions in I.kappa.B.alpha. essential for signaling and degradation (Brown et al. Science 267:1485-1487 (1995); Brockman et al. Mol. Cell. Biol. 15:2809-2818 (1995)).